Press Releases for 1994

Gene Predicts Bone Density, Those at Risk for Osteoporosis

Researchers have found a gene that may help to identify, early in life, individuals
at high risk for osteoporosis. This gene strongly influences bone density,
an important determinant of the risk of osteoporosis. Osteoporosis (porous,
weak bone) affects more than 25 million people in the U.S.; it is the major
underlying cause of bone fractures in postmenopausal women and the elderly.
Osteoporosis usually results from two factors: the peak bone strength (density)
attained in early life, and how rapidly a person loses bone in later life. "The
prospect of having a genetic marker of bone density that would permit early
intervention to prevent osteoporosis is extremely exciting," says Dr. Lawrence
E. Shulman, Director of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases at the National Institutes of Health, which funded the study.

Although heredity has long been suspected of playing a role in bone density,
until now genes responsible for this trait have not been identified. As reported
in the January 20th issue of the scientific journal Nature, Dr. John
A. Eisman and colleagues at the Garvan Institute of Medical Research in Sydney,
Australia, have now found that a single gene can account for up to 75 percent
of the total genetic effect on bone density. This gene codes for the vitamin
D receptor (VDR), a protein that enables vitamin D to exert its actions on
bone and on calcium metabolism. Non-genetic factors such as hormones, calcium
intake, and exercise also influence the density of bone.

Eisman and his colleagues measured bone densities in 70 pairs of identical
twins and 55 nonidentical twins. The researchers found that identical twins,
who share 100 percent of their genes, had more similar bone densities than
did nonidentical twins, who do not share all genes. The researchers also found
that there are two forms (alleles) of the VDR gene, one called "B" and the
other called "b." Normal people have one copy of the VDR gene from each parent,
and thus may have either the BB, Bb, or bb combination. The researchers then
looked at the effect of the two forms of the VDR gene on bone density. They
found a strong link between the "B" version of the VDR gene and low bone density
in the spine and femur (thigh bone at the hip). Bone density was lowest in
those with the BB combination, intermediate in those with Bb, and highest in
those with bb. Nonidentical twins that had the same alleles of the VDR gene
were similar to identical twins in this regard, thus strengthening the importance
of these receptor genes to bone density. It is not yet clear how the difference
between the two forms of the VDR gene could affect bone density.

The researchers also examined 311 unrelated healthy women from the Sydney
area. In this second population, the vitamin D receptor gene was also found
to be a strong predictor of bone density, and again the "B" allele was associated
with lower bone density. Eisman and colleagues predict that women with BB,
having low bone density in early life, will, when they start to lose bone as
they age, reach the "fracture threshold" of low bone density in the spine 11
years earlier, and in the hip 8 years earlier, than those with bb. The latter
translates to a four-fold increase in the risk of hip fracture for BB individuals
as compared to those with bb.

These findings need to be extended to other and larger populations in the
United States and elsewhere. They may provide an important explanation for
the wide variation in bone density, not only among individuals, but also among
various ethnic groups. African-American women in the United States, for example,
develop approximately 10 percent greater peak bone mass by age 35 than do Caucasian
women.

Research is also needed to uncover the precise role of the vitamin D receptor
in regulating bone density. These investigations open new frontiers in research
on the underlying causes of osteoporosis, and in particular the critical role
of vitamin D in bone formation and metabolism. They could also pave the way
for developing new targeted approaches to the prevention and treatment of this
common and debilitating disease, a major public health problem in the United
States.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases,
a component of the National Institutes of Health, leads and coordinates the
Federal research effort in osteoporosis and related bone disorders by supporting
research projects, research training, clinical trials, and epidemiological
studies, and by disseminating information on research results.